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  Absorption Model

First-Order

  Volume of Distribution

Minimal PBPK (Method 1)

  Route of Elimination

CYP3A4 (fm = 0.50); renal clearance (fe = 0.1)

  Perpetrator DDI

• CYP2D6 Inhibitor

  Validation

• Three clinical studies describing Quinine PK were identified for model verification.
• Three clinical DDI studies where quinine was the victim of CYP-mediated DDIs were used to verify the PBPK model.  All studies were well recovered with simulated Cmax and AUC GMRs within 1.5-fold of the observed

  Limitations

• The Simcyp quinine PBPK model was able to recover interactions CYP3A inducers and inhibitors with reasonable accuracy.
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time.

  Updates in V19

• Updated in vitro­ data
  • fup: 0.199 -> 0.37
  • Caco-2 A -> B Permeability: 70 x 10-6 cm/s -> 39 x 10-6 cm/s
  • Propranolol reference Permeability: 101 x 10-6 cm/s -> 45 x 10-6 cm/s
• Minimal PBPK with Vss predicted through Method 1
  • Updated retrograde clearance

Absorption Model

• First-Order

Volume of Distribution 

• Full PBPK (Method 2)

Routes of Elimination

• 89% MAO (entered using ‘user-UGT’ as a surrogate in the Simulator), 11% CYP2D6

Perpetrator DDI

• CYP1A2 Inhibitor (in vitro)

Validation

•  6 studies with single (15 to 45 mg) and multiple (15 mg QD) dosing. 100% of Cmax and AUC values within 1.5-fold.
• No clinical DDI studies to verify contribution of metabolic routes

Limitations

•  The active metabolites of primaquine have not characterized due to their instability. Therefore, a PBPK model for active metabolites cannot be developed in their own right.
• Qualitative data suggests a role of P-gp, however, Jmax and Km values have not been measured.
• There is evidence of enantiomer specific metabolism for primaquine which has not been considered in the current model.

Updates in Version 19

• Updated in vitro protein and blood binding data and subsequent back calculation of CLint (retrograde approach)
  •  f_u: 0.19 -> 0.26
  • B:P: 1 -> 0.82

• Converted from minimal PBPK model to full PBPK model

  Absorption Model

First-Order

  Volume of Distribution

Full PBPK (Method 2)

  Route of Elimination

CYP3A4 (fm =100); renal clearance (fe = 0.05)

  Perpetrator DDI

• CYP2C9 Inhibitor
• CYP2D6 Inhibitor
• CYP3A4 Inhibitor

  Validation

• Six clinical studies describing single and multiple dose exposure of mefloquine were used the verify the PBPK model.  Most of the studies (83%) were within 1.5-fold, with all simulations falling within 2-fold of the observed values. 
• Two clinical DDI studies where mefloquine was the victim of a CYP3A4-mediated DDI were accurately recovered using the PBPK model.

  Limitations

• Only profiles of plasma concentrations assessed, many studies report blood concentrations​
• Mefloquine has significant uptake into erythrocytes and haematocrit levels typically not reported​
• Could be important in disease population (Possible time-varying B/P for Malaria patients?)​
• Cmax for doses > 750 mg over predicted ​
• fa possibly decreases with dose, more data needed to fully determine the cause​
• Most literature data extracted from graphs of mean data, difficulty determining accurate early time points due to poor image quality​
• Verification needed for perpetrator DDI assessment as literature data is unavailable at this time

  Updates in V19

• Updated in vitro­ data

• • fu_p: 0.016 -> 0.015

• • B:P ratio 1.7 -> 1.1 and subsequent re-calculation of CLint using the retrograde approach
• Converted model to full PBPK distribution model with Vss predicted through Method 2
• Sensitivity analysis of ka